ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4327C>T (p.Arg1443Ter)

dbSNP: rs41293455
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 46
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000019244 SCV000282327 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000048523 SCV000076536 pathogenic Hereditary breast ovarian cancer syndrome 2024-01-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1443*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 16030099, 19656415, 22798144, 23233716). It is commonly reported in individuals of French Canadian ancestry (PMID: 10422801, 11250694, 15883839, 20694749). This variant is also known as 4446C>T. ClinVar contains an entry for this variant (Variation ID: 17675). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131880 SCV000186935 pathogenic Hereditary cancer-predisposing syndrome 2021-11-24 criteria provided, single submitter clinical testing The p.R1443* pathogenic mutation (also known as c.4327C>T), located in coding exon 11 of the BRCA1 gene, results from a C to T substitution at nucleotide position 4327. This changes the amino acid from an arginine to a stop codon within coding exon 11. This mutation is a well-known French Canadian founder mutation and has been reported in numerous breast and/or ovarian cancer families to date (Ferla R et al. Ann. Oncol. 2007 Jun;18 Suppl 6:vi93-8; Ghadirian P et al. Clin. Genet. 2009 Nov;76(5):421-6; Janavicius R et al. EPMA J. 2010 Sep;1(3):397-412; Zhang S et al. Gynecol. Oncol. 2011 May;121(2):353-7). In addition to French Canadians, this mutation has also been identified in multiple other populations (McKean-Cowdin R et al. Hum. Genet. 2005 May;116(6):497-506; Donenberg T et al. Breast Cancer Res. Treat. 2016 Aug;159(1):131-8; Jalkh N et al. BMC Med Genomics 2017 Feb;10(1):8; Palmero EI et al. Sci Rep. 2018 Jun;8(1):9188; Singh J et al. Breast Cancer Res. Treat. 2018 Jul;170(1):189-196). Of note, this alteration is also designated as 4446C>T and R1443X in some published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000235131 SCV000210173 pathogenic not provided 2019-11-04 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 4446C>T; This variant is associated with the following publications: (PMID: 23233716, 26028024, 25371446, 27463008, 28127413, 19656415, 9625424, 7493024, 8533757, 28111427, 29446198, 16905680, 25525159, 18680205, 23341105, 22401979, 15382066, 20694749, 15883839, 10090482, 23199084, 17148771, 11307153, 10486320, 7894491, 21324516, 27469594, 27184744, 27393621, 26541979, 28049106, 27783335, 16030099, 25236687, 27533253, 26976419, 21120943, 27221827, 26911350, 25504618, 17688236, 27286788, 25085752, 27553291, 28283652, 28392550, 19863560, 15726418, 25652403, 17591843, 19241424, 11179017, 17221156, 22798144, 9792861, 10682662, 26295337, 19329713, 16417652, 10422801, 15951958, 18821011, 10984458, 8990217, 21203900, 8571953, 28985766, 26681312, 28993434, 29907814, 29470806, 28724667, 30702160, 30630528, 30078507, 30720243, 30322717, 30093976, 31090900, 32467295, 33646313, 11597388, 31447099, 31825140, 32341426, 32885271, 30875412, 31742824, 33087929)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000735445 SCV000219242 pathogenic Breast and/or ovarian cancer 2023-06-23 criteria provided, single submitter clinical testing
Counsyl RCV000019244 SCV000220762 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2014-10-02 criteria provided, single submitter literature only
Eurofins Ntd Llc (ga) RCV000235131 SCV000225648 pathogenic not provided 2018-05-25 criteria provided, single submitter clinical testing
Michigan Medical Genetics Laboratories, University of Michigan RCV000019244 SCV000267710 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2016-04-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235131 SCV000296337 pathogenic not provided 2023-07-06 criteria provided, single submitter clinical testing The BRCA1 c.4327C>T (p.Arg1443*) variant causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in individuals with breast cancer (PMID: 33646313 (2021), 32885271 (2021), 32854451 (2020), 32341426 (2020), 32029870 (2020), 28724667 (2017)) and endometrial cancer (PMID: 28049106 (2017)). This variant has also been described as a French founder mutation (PMID: 23199084 (2010). The frequency of this variant in the general population, 0.000085 (3/35428 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
GeneKor MSA RCV000239083 SCV000296802 pathogenic not specified 2016-07-01 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000019244 SCV000325921 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-10-02 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000131880 SCV000537634 pathogenic Hereditary cancer-predisposing syndrome 2023-05-09 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 12 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 30 individuals affected with breast, ovarian and uterine cancer (PMID: 7894491, 10422801, 10682662, 11179017, 15726418, 17221156, 19656415, 19863560, 20104584, 21324516, 22798144, 26681312, 27553291, 28724667, 28993434, 29470806, 33471991; Leiden Open Variation Database DB-ID BRCA1_000312). A breast cancer case-control meta-analysis detected this variant in 9/41890 cases and 1/41607 unaffected individuals with an OR 8.3 (95% CI 1.05-16.0) (PMID: 28283652). This variant has been detected in over 100 suspected hereditary breast and ovarian cancer families (PMID: 7493024, 16030099, 18821011, 19241424, 19329713, 21203900, 23233716, 29907814), in which haplotype analyses suggest that this was a founder mutation in the French-Canadian population and also arose independently worldwide (PMID: 9792861, 15883839, 23199084). This variant has been identified in 7/282760 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Baylor Genetics RCV000159989 SCV000540934 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Genologica Medica RCV000019244 SCV000577931 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2017-01-01 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine, Queen's University RCV000048523 SCV000588057 pathogenic Hereditary breast ovarian cancer syndrome 2017-04-20 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000019244 SCV000593678 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2016-11-29 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000239083 SCV000602710 pathogenic not specified 2019-02-21 criteria provided, single submitter clinical testing The BRCA1 c.4327C>T; p.Arg1443Ter variant (rs41293455), also known as 4446C>T for traditional nomenclature, is reported in the literature in multiple individuals with hereditary breast and ovarian cancer syndrome (Castilla 1994, de Jonge 2017, Rashid 2016, Sun 2017, Susswein 2016, Zhang 2011). This variant is also described as a founder variant in the French Canadian population (Cavallone 2010, Neuhausen 2000, Tonin 1999, Vezina 2005). It is reported by multiple laboratories in ClinVar (Variation ID: 17675), and found in the general population with a low overall allele frequency of 0.002% (6/246148 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Castilla LH et al. Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer. Nat Genet. 1994 Dec;8(4):387-91. Cavallone L et al. Comprehensive BRCA1 and BRCA2 mutation analyses and review of French Canadian families with at least three cases of breast cancer. Fam Cancer. 2010 Dec;9(4):507-17. de Jonge MM et al. Linking uterine serous carcinoma to BRCA1/2-associated cancer syndrome: A meta-analysis and case report. Eur J Cancer. 2017 Feb;72:215-225. Neuhausen SL. Founder populations and their uses for breast cancer genetics. Breast Cancer Res. 2000;2(2):77-81. Rashid MU et al. High prevalence and predominance of BRCA1 germline mutations in Pakistani triple-negative breast cancer patients. BMC Cancer. 2016 Aug 23;16(1):673. Sun J et al. Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients. Clin Cancer Res. 2017 Oct 15;23(20):6113-6119. Susswein LR et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016 Aug;18(8):823-32. Tonin PN et al. Founder BRCA1 and BRCA2 mutations in French Canadian ovarian cancer cases unselected for family history. Clin Genet. 1999 May;55(5):318-24. Vezina H et al. Molecular and genealogical characterization of the R1443X BRCA1 mutation in high-risk French-Canadian breast/ovarian cancer families. Hum Genet. 2005 Jul;117(2-3):119-32. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011 May 1;121(2):353-7.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000048523 SCV000605740 pathogenic Hereditary breast ovarian cancer syndrome 2019-04-24 criteria provided, single submitter clinical testing The p.Arg1443X variant in BRCA1 has been previously reported in >100 individuals with BRCA1-associated cancers (Vézina 2005, Hall 2009). It has also been identified in 3/35428 Latino chromosomes by the Genome Aggregation Database (GnomAD, http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 1443, which is predicted to lead to a truncated or absent protein. In addition, functional studies provide some evidence that this variant results in a truncated protein (Caligo 2009). Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in individuals with hereditary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282327.1). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1, PS3_Supporting, PS4.
Fulgent Genetics, Fulgent Genetics RCV000763000 SCV000611253 pathogenic Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S 2021-10-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000048523 SCV000699132 pathogenic Hereditary breast ovarian cancer syndrome 2016-08-15 criteria provided, single submitter clinical testing Variant summary: The c.4327C>T (p.Arg1443X) variant in BRCA1 gene is a nonsense mutation. The mutation is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.000016 (2/121390 chrs tested). This frequency does not exceed the maximal expected allele frequency for a pathogenic variant in BRCA1 (0.001). The variant has been reported in multiple HBOC families and was shown to segregate with disease phenotype. It has been classified as pathogenic by multiple reputable databases/clinical laboratories. Taken together, the variant was classified as Pathogenic.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000019244 SCV000743394 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2014-10-08 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000019244 SCV000744615 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-09-21 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000235131 SCV000778740 pathogenic not provided 2023-05-02 criteria provided, single submitter clinical testing PP5, PM2, PS4_moderate, PVS1
Fulgent Genetics, Fulgent Genetics RCV000763000 SCV000893445 pathogenic Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S 2018-10-31 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000019244 SCV001434962 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2018-10-12 criteria provided, single submitter clinical testing This rare nonsense variant c.4327C>T (p.Arg1443*) in the BRCA1 gene is extremely rare in public databases and is predicted to introduce a premature translation termination codon. This variant is considered to be a founder mutation (PMID 15883839 ) and has been observed in multiple unrelated individuals with breast cancer (PMID 10422801,21324516, 7894491). Therefore, this c.4327C>T (p.Arg1443*) variant in the BRCA1 gene is classified as pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital RCV000235131 SCV001450289 pathogenic not provided 2015-08-19 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000235131 SCV001762197 pathogenic not provided 2021-06-17 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000019244 SCV001934263 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2020-10-23 criteria provided, single submitter clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State RCV000048523 SCV002025939 pathogenic Hereditary breast ovarian cancer syndrome 2021-11-16 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000131880 SCV002538287 pathogenic Hereditary cancer-predisposing syndrome 2021-11-09 criteria provided, single submitter curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000235131 SCV002550977 pathogenic not provided 2023-08-15 criteria provided, single submitter clinical testing
Revvity Omics, Revvity Omics RCV000235131 SCV003809801 pathogenic not provided 2023-11-03 criteria provided, single submitter clinical testing
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg RCV000235131 SCV004042699 pathogenic not provided 2023-10-17 criteria provided, single submitter clinical testing This variant has been identified by standard clinical testing. female patient with breast cancer Selected ACMG criteria: Not enough evidence
Baylor Genetics RCV000019244 SCV004215050 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2023-07-24 criteria provided, single submitter clinical testing
OMIM RCV000019244 SCV000039532 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 1994-12-01 no assertion criteria provided literature only
Sharing Clinical Reports Project (SCRP) RCV000019244 SCV000109372 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2013-11-14 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000019244 SCV000145057 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2002-05-29 no assertion criteria provided clinical testing
Bioinformatics dept., Datar Cancer Genetics Limited, India RCV000159989 SCV000280026 pathogenic Familial cancer of breast no assertion criteria provided case-control
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto RCV000048523 SCV000587391 pathogenic Hereditary breast ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001353404 SCV000591505 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The p.Arg1443X variant has been previously and extensively reported in the literature. In two selected publications, this variant was identified in 18 of 294 individuals with hereditary breast and ovarian cancer (Selected publications: Tonin 1998, Castilla 1994). This variant was identified as a founder French-Canadian mutation and a common haplotype was described; multiple individuals from these families had breast or ovarian cancers; additional data suggest this variant may also have arisen independently at least three times. The variant is described 83 times in the UMD database as "causal" and 126 times in the BIC database as clinically important. The p.Arg1443X variant leads to a premature stop codon at position 1443, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of hereditary breast and ovarian cancer. In summary, based on the above information, this variant is classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000019244 SCV000733611 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735445 SCV000863581 pathogenic Breast and/or ovarian cancer 2015-12-07 no assertion criteria provided clinical testing
GenomeConnect - Invitae Patient Insights Network RCV000048523 SCV001749723 not provided Hereditary breast ovarian cancer syndrome no assertion provided phenotyping only Variant interpreted as Pathogenic and reported on 04-30-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute RCV000235131 SCV001905764 pathogenic not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000235131 SCV001958778 pathogenic not provided no assertion criteria provided clinical testing
BRCAlab, Lund University RCV000019244 SCV002588810 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2022-08-26 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.